Diindole compounds useful in treatment of nervous system disorders

ABSTRACT

The invention provides bridged diindole compounds, related pharmaceutical compositions and methods of use thereof, for the prevention, palliation and/or treatment of nervous system disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of co-pending U.S.provisional patent application Ser. No. 62/343,887, filed on Jun. 1,2016, which application is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to bridged diindole compounds andpharmaceutical compositions and methods of use thereof, as antagonistsand partial antagonists at N-methyl-D-aspartate (NMDAR) and at itssubunit isoforms, including the NR2A and NR2B subunits, for theprevention, palliation and/or treatment of nervous system disorders orconditions and for the induction of anesthesia, in humans and inanimals. Such disorders or conditions include epilepsies, seizures,conduction disturbances and electroconvulsive disorders, pain,fibromyalgia, affective disorders such as bipolar disorder anddepression, autism, schizophrenia, Parkinson's disease, Alzheimer'sdisease, attention deficit disorder, attention deficit hyperactivitydisorder, and neurodegeneration of all types, manifestations andorigins.

BACKGROUND OF THE INVENTION

Learning and memory, nerve development, Alzheimer's disease, epilepsy,seizures and other electroconvulsive disorders, pain, fibromyalgia,schizophrenia and psychosis, depression and other affective disorders,autism, Parkinson's disease, attention deficit disorder, attentiondeficit hyperactivity disorder, anesthesia, and neurodegeneration haveall been linked to the activity and regulation of theN-methyl-D-aspartate receptor (NMDAR; 1,2). The NMDAR, a non-selectiveion channel present on many types of nerve cells, regulates and modifiesnerve growth and is directly linked to signaling and nerve activity inthe brain. The development of NMDAR modulators, including NMDARantagonists and partial NMDAR antagonists, as new diagnostic agents andnew therapeutic drugs, is a promising area of research.

A number of bridged diindoles that are structurally distinct fromcompounds known to modify NMDAR activity, as well as from knowntherapeutic drugs, have been identified as potential NMDAR ligands,partial NMDAR antagonists, NMDAR antagonists, and modulators of NMDARactivity. Computer-based (in silico) modeling studies that assess theaffinity and specificity of the chemical interactions between smallmolecules and large biological molecules, such as the NMDAR, reveal thatthese novel compounds interact with NMDAR at specific receptor bindingsites in unique ways not previously reported in the literature. Studiesreveal that these compounds likely act as NMDAR antagonists or partialNMDAR antagonists. This includes activity as antagonists at one or moreNMDAR NR2 isoform receptor sites, including NMDAR NR2A and NR2B.

Preliminary in silico modeling data indicate the existence of multipleNMDAR binding sites for these compounds, suggesting that they could beuseful for regulating multiple nervous system and brain functions anddiseases. In silico modeling experiments using computer programs such asDiscovery Studio and AutoDock 4 for modeling interactions of thecompounds with crystal structure models of the NMDAR reveal that thesecompounds bind specifically and with high affinity to sites on the NMDARincluding subunit NR2 isoforms, such as NMDAR NR2A and NR2B, at sitesthat include the entrance to a cavity that also contains the activatingagonist (glutamate) binding site.

Bridged diindole and bis-diindole compounds and their derivatives, bothsynthetic and naturally occurring, have been reported. Most of thesehave physical-chemical properties and commercial utility completelyunrelated to biological or pharmacological activity, as evidenced bytheir use as combustion modifiers, polymerization initiators andpromoters, electrical conductors, and glass materials (3,4). A number ofbridged diindole compounds, including those with a methylene, a ketone,a sulfide, and a sulfone as bridging moieties, do have biologicalactivity. However, their chemical structures are clearly distinct fromthose contemplated in the present invention, as are their purportedbiological activities, which are completely distinct from the NMDARantagonist activity and nervous system effects contemplated by thecompounds revealed in the present invention. These include: DNA-bindingand alkylating agents proposed for cancer treatment (5,6); antibioticsand antibacterial agents (7-9); and biological effects related to theserotonin (5-HT) receptor (10,11).

A number of drugs that modulate NMDAR activity, including NMDARantagonists, are available or are under development for treating theseaforementioned NMDAR-related nervous system pathologies (12). Theseinclude: Alzheimer's disease and other memory disorders (13); statusepilepticus and other electroconvulsive disorders (14); pain-relateddisorders (15,16); schizophrenia (17); autism (18); and depression andother mood disorders (19-21), including the effects of NMDAR activitymodulation on depression and mood disorders by molecular modelingmethods (22).

Given the enormous therapeutic potential of NMDAR antagonists aspalliatives and treatments for nervous system disorders, severalpublished patents and patent applications teach the synthesis and use ofnovel NMDAR modulators, including NMDAR antagonists, as therapeuticagents for nervous system disorders. Although completely unrelatedchemically to the compounds that are the subject matter of the presentinvention, these patents and applications describe specific NMDARantagonists, discrete NMDAR subunit antagonists, and the proposedtherapeutic activity of NMDAR ligands for nervous system pathologies(23-27).

However, many of these agents have a number of shortcomings. Forinstance, the agents may be poorly soluble in aqueous and biologicalfluids or may be extremely hygroscopic, thereby complicating theirformulation and delivery to patients and to their active sites.Moreover, the agents may be chemically and/or physically unstable. Theymay be inherently toxic, or they may undergo conversion to toxicdegradants in storage or when metabolized. Many of these agents are notabsorbed by the oral route, thus requiring more expensive and invasivemodes of administration, such as needle injection. Of even greaterimportance is that patients may become refractory to these drugs overtime. Many patients require multi-drug therapy in order to achieve adesired clinical effect. In addition, many current NMDAR-modulatingagents cause unwanted side effects, neurotoxicities, and druginteractions.

As an example, the drug treatments currently available for one subset ofthe aforementioned, NMDA-influenced nervous system pathologies, epilepsyand other electroconvulsive disorders, exemplify many of thesetherapeutic drug limitations. These include refractory loss of drugeffect, the need for multiple drug therapy, undesirable side effects,drug and dietary interactions, and a decrease in patient quality of life(28). As novel NMDAR-modulating compounds, such as those that areincluded in the subject matter of the present invention, are identifiedand developed, the clinician will have expanded pharmaceutical optionswhen designing an effective treatment protocol for each patient. Thispossibility clearly underscores the utility of the present invention.

The need for novel compounds that interact with the NMDAR as therapeuticagents is further underscored by the fact that many NMDA-modulatingcompounds, such as anti-epilepsy compounds, are effective in thetreatment of other central nervous system disorders, including bipolardisorder, fibromyalgia, migraine prophylaxis, neuropathic pain, andchronic pain, alone or in combination with other biologically activeagents. These novel compounds would ideally interact chemically with theNMDAR in a manner that is distinct from current NMDAR-modulating agentsand ligands. They might also interact with one or more sites in thecentral nervous system that are distinct from the purported sites andmodes of action of current agents.

SUMMARY OF THE INVENTION

After in silico investigation, it has been discovered bridged diindolecompounds of the type represented in Formula I (below) avidly interactwith and bind to the NMDAR, and to its subunits, including the NR2A andNR2B subunits, and likely act as antagonists or partial antagonists toNMDAR. As NMDAR antagonists and partial antagonists, these compounds,whose pharmacological activity on the central and peripheral nervoussystems has never been reported, are useful as preventative, palliative,and therapeutic agents for nervous system disorders and conditions,including conditions such as Alzheimer's disease, epilepsy, seizures andother electroconvulsive disorders, pain, fibromyalgia, schizophrenia andpsychosis, depression and other affective disorders, autism, Parkinson'sdisease, attention deficit disorder, attention deficit hyperactivitydisorder, and neurodegeneration. They are also useful as anestheticagents or anesthetic adjuncts.

In one aspect, the invention relates to a compound having a structuralformula as follows:

where, X is selected from the group consisting of —O—, —S—, —N(H)—,—Se—, —Si—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, (cis)-CH═CH—,(trans)-CH═CH—, —CH═CH—CH₂—, —CH₂—CH═CH—, —N═N—, —N═CH—, —CH═N—, —C(S)—,—N(H)S(O)—, —N(H)SO₂—, —N(H)O—, —N(H)S—, —S(O)—, —SO₂—, —PO₄—, —C(O)—,—CH₂—, —CF₂—, —C(CH₃)₂—, and a covalent bond;

-   Y₁ and Y₂ are each independently selected from the group consisting    of hydrogen, deuterium, and tritium;-   n is an integer from 0 to 6; and-   R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are each independently selected    from the group consisting of hydrogen, hydroxyl, carboxyl, amino,    aminoalkyl, nitro, hydroxymethyl, hydroxyalkyl, acetate, propionate,    butyrate, thiol, thioalkyl, nitrile, a halogen, trifluoromethyl,    methoxy, ethoxy, phenyl, guanidino, amidino, amide, alkylamide,    sulfate, phosphate, imidazole, thiazole, a substituted or    unsubstituted C₁₋₁₀ alkyl, a substituted or unsubstituted branched    C₃₋₁₀ alkyl, a substituted or unsubstituted C₃₋₁₀ cycloalkyl, a    substituted or unsubstituted arylalkyl, and a covalent bond.

In preferred embodiments, the compound of the invention comprises athiodiindole or an ethylenediindole. In a feature, the compoundeffectively inhibits a function of a N-methyl-D-aspartate receptor(NMDAR) in an animal, such as an mammal including homo sapiens. Thecompound, in some embodiments, binds at least one of NMDAR's subunitisoforms, the NR2A and NR2B subunits.

In a further aspect, the invention relates to a pharmaceuticalcomposition, comprising the compound of the invention as describedherein, and a pharmaceutically acceptable excipient, carrier, ordiluent. When referring to the compound of the invention, it is intendedto include all resolved enantiomers, diastereomers, tautomers, salts,solvates and polymorphic forms of Formula I. The pharmaceuticalcomposition of the invention can be in an admixture, dosage form,delivery system, food, or vehicle with biologically and pharmaceuticallyacceptable carriers, adjuvants, excipients, and diluents.

According to a further aspect of the invention, a method is provided totreat (including to prevent and/or ameliorate) a disorder orpathological condition in a subject, which may be a human or an animalpatient. The method includes administering to a subject in need thereofa therapeutically effective amount of the pharmaceutical composition ofthe invention. The disorder or condition includes epilepsies, seizures,conduction disturbances and electroconvulsive disorders, pain (e.g.,neuropathic and chromic pains), fibromyalgia, affective disorders suchas bipolar disorder and depressive disorders including major depression,depression, dysthymia, cyclothymia, and post-partum depression, autism,schizophrenia, Parkinson's disease, Alzheimer's disease and otherdementias, attention deficit disorder, attention deficit hyperactivitydisorder, and neurodegeneration of all types, manifestations and originsincluding post-stroke neurodegeneration and related sequelae.

In a feature, the therapeutically effective amount of the pharmaceuticalcomposition of the invention effectively inhibits a function of theN-methyl-D-aspartate receptor (NMDAR) in the subject. In variousembodiments, the therapeutically effective amount is from about 0.1mg/kg to about 300 mg/kg.

According to yet another aspect of the invention, a method is providedfor inducing or augmenting anesthesia. The method includes a step ofadministering to a subject in need thereof a therapeutically effectiveamount of the pharmaceutical composition of the invention, alone or incombination with other agents, drugs, foods, supplements, or procedures.

Additional advantages of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription. As will be realized, the invention is capable of other anddifferent embodiments, and its several details are capable ofmodifications in various obvious respects, all without departing fromthe present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates hydrogen-bonding characteristics of the NMDAr NR2asubunit cavity into which the model compounds were bound according tothe invention.

FIG. 2 illustrates overlay of bridged diindole and comparisondiaminodiphenyl compounds and derivatives whose orientation and RMSdeviation overlap lead to similar binding interactions with the NMDArNR2A subunit. (The compounds include dapsone, diaminobenzophenone,diaminodiphenyl methane, oxydianiline, diaminodiphenyl sulfide,ethylenedianiline, ethylenediindole, thiodiindole, methylenebis(chloroaniline), and methylene bis(2,6-dimethylaniline).

FIG. 3 illustrates aromatic characteristics of the model NMDAR NR2Asubunit cavity in which the affinity and binding characteristics ofbridged diindole and diaminodiphenyl compounds were assessed in silico,according principles of the present invention.

FIGS. 4A and 4B illustrate binding orientations of4,4′-ethylenedianiline and ethylene diindole in (4A); and4,4′-thiodianiline and thiodiindole in (4B).

FIGS. 5A and 5B are coordinate maps of the proposed binding interactionsof diindole compounds with the NMDAR NR2A subunit: with ethylenediindole in (5A) and thiodiindole in (5B).

FIGS. 6A-6D show modeled interactions between specific amino acidresidues within the NMDAR binding site and: (6A) thiodianiline, (6B)thiodiindole, (6C) ethylene dianiline, and (6D) ethylenediindole.

DETAILED DESCRIPTION OF THE INVENTION I. Definition

Unless otherwise noted, technical terms are used according toconventional usage. Definitions of common terms in molecular biology maybe found, for example, in Lewin's Genes XII, published by Jones andBartlett Learning, 2018 (ISBN 1284104494), J. Krebs et al. (eds.) andother similar technical references.

As used herein, “about” means within plus or minus 10%. For example,“about 1” means “0.9 to 1.1”, “about 2%” means “1.8% to 2.2%”, “about 2%to 3%” means “1.8% to 3.3%”, and “about 3% to about 4%” means “2.7% to4.4%.”

As used herein, the term “subject” refers to any animal (e.g., amammal), including, but not limited to humans, non-human primates,rodents, and the like, which is to be the recipient of a particulartreatment. Typically, the terms “subject” and “patient” are usedinterchangeably herein in reference to a human subject.

As used herein, terms such as “treating” or “treatment” or “to treat” or“alleviating” or “to alleviate” as used herein refer to both (1)therapeutic measures that cure, slow down, lessen symptoms of, and/orhalt progression of a diagnosed pathologic condition or disorder and (2)prophylactic or preventative measures that prevent or slow thedevelopment of a targeted pathologic condition or disorder. Thus thosein need of treatment include those already with the disorder; thoseprone to have the disorder; and those in whom the disorder is to beprevented.

As used herein, the terms “inhibiting”, “to inhibit” and theirgrammatical equivalents, when used in the context of a bioactivity,refer to a down-regulation of the bioactivity, which may reduce oreliminate the targeted function, such as the production of a protein orthe phosphorylation of a molecule. In particular embodiments, inhibitionmay refer to a reduction of about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%or 95% of the targeted activity. When used in the context of a disorderor disease, the terms refer to success at preventing or significantlydelaying the onset of symptoms, alleviating symptoms, or eliminating thedisease, condition or disorder.

The term “pharmaceutically acceptable excipient, carrier, or diluent” asused herein means a pharmaceutically-acceptable material, composition orvehicle, such as a liquid or solid filler, diluent, excipient, solventor encapsulating material, involved in carrying or transporting thesubject pharmaceutical agent from one organ, or portion of the body, toanother organ, or portion of the body. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of theformulation and not injurious to the patient. Some examples of materialswhich can serve as pharmaceutically-acceptable carriers include: sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients, such as cocoa butter andsuppository waxes; oils, such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil; glycols, such aspropylene glycol; polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations. Wettingagents, emulsifiers and lubricants, such as sodium lauryl sulfate,magnesium stearate, and polyethylene oxide-polypropylene oxide copolymeras well as coloring agents, release agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the compositions.

II. Description

A series of bridged diindole compounds were identified through in silicomodeling studies as interacting avidly and discretely with theN-methyl-D-aspartate receptor (NMDAR), including the NMDAR subunitisotypes NR2A and NR2B, located in the mammalian nervous system,apparently resulting in NMDA receptor antagonism or partial antagonsim.Such an in silico model is often predictive of those compounds that areactive in vivo, and those that are inactive in vivo. Structure-activityrelationship (SAR) studies have afforded information related to thechemical structural motifs and requirements for in silico binding andlikely in vivo activity.

The subject matter of the present invention relates to bridged diindolecompounds according to Formula I and their use for the prevention,palliation and/or treatment of seizures, conduction disturbances andelectroconvulsive disorders of all types, manifestations and origins, inhumans and other mammals, and for pain, affective disorders such asbipolar disorder and depression, autism, schizophrenia, Parkinson'sdisease, attention deficit disorder, attention deficit hyperactivitydisorder, and neurodegeneration of all types, manifestations andorigins, and for the induction of anesthesia, in a human or othermammal.

Specifically, the present invention provides pharmaceutical preparationsand the uses thereof for the prevention, palliation and/or treatment ofthe aforementioned nervous system pathologies by administering apharmaceutically effective amount of a therapeutic compound according toFormula I, as described above.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of epilepsy, seizure, orother electroconvulsive disorder.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of bipolar disorder.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of depressive disorders,including major depression, depression, dysthymia, cyclothymia, andpost-partum depression.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of neuropathic pain.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of chronic pain.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of fibromyalgia.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of neurodegeneration.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of autism.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of schizophrenia.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of central nervous systemdamage and related sequelae secondary to stroke.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of Parkinson's disease.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal in need of treatment or prevention of an attention deficitdisorder.

Embodiments include administering an effective amount of a compoundaccording to Formula I, an analog, derivative, prodrug, or apharmaceutically accepted salt, complex, solvate, or polymorph thereof,to a mammal, alone or in combination with other agents or procedures,for the induction or maintenance of anesthesia.

It has been discovered that compounds according to Formula I avidlyinteract with and bind to the NMDAR, and with its subunits and itssubunit isoforms, including the NR2A and NR2B subunits, and may act asantagonists and partial antagonists to the NMDAR. As NMDAR antagonistsand partial antagonists, these compounds, whose central and peripheralnervous system pharmacological activity has never been reported, arelikely to be useful as preventative, palliative, and therapeutic agentsfor nervous system conditions, including central nervous systemconditions, such as Alzheimer's disease, epilepsy, seizures and otherelectroconvulsive disorders, pain, fibromyalgia, schizophrenia andpsychosis, depression and other affective disorders, autism, Parkinson'sdisease, attention deficit disorder, attention deficit hyperactivitydisorder, and neurodegeneration of all types and manifestationsirrespective of the origin of the ailment in a subject in need thereofincluding humans and other mammals. It is contemplated that theinventive compositions can be employed for preventing and/or treatingother conduction disturbances of the central nervous system (CNS), andthe emotional, cognitive, and motor symptoms resulting there from.

In an embodiment of the present invention, the inventive compositionsare administered to a subject in need thereof to prevent or treat thosedisturbances of the nervous system as mentioned above, of either or bothan acute or chronic nature, of unknown origin or secondary to conditionssuch as, but not limited to: surgery, irradiation, or other manipulationof the brain and/or CNS; alcohol, benzodiazepine, barbiturate or otherdrug or chemical withdrawal; exposure to exogenous drugs and/orchemicals; acute or chronic injury or trauma; stroke or cerebrovascularaccident; fever; meningitis or other CNS inflammation or infection; orelectroconvulsive therapy.

In practicing the present invention, the compound having Formula I, oran analog, derivative, prodrug, or a pharmaceutically accepted salt,complex, solvate, or polymorph thereof, is formulated intopharmaceutical compositions.

The compound of Formula I includes all resolved enantiomers,diastereoisomers, tautomers, salts, solvates and polymorphic formsthereof. Such salts include, but are not limited to, the following:inorganic acid addition salts such as hydrochloride, hydrobromide,sulfate, phosphate, and nitrate; organic acid addition salts such asacetate, galactarate, propionate, succinate, lactate, glycolate, malate,tartrate, citrate, maleate, fumarate, methanesulfonate, salicylate,p-toluenesulfonate, benzenesulfonate, and ascorbate; salts with acidicamino acids such as aspartate and glutamate; base addition salts, suchas the salts of acidic compounds according to Formula I formed by theaddition of inorganic based such as an alkali hydroxide or an aminebase. The salts may in some cases be hydrates or solvates with water,acetone, alcohols, and other solvents, and combinations thereof, andmixtures thereof. Salt forms of compounds according to Formula I can beprepared by methods known to those skilled in the art, such as bydissolving, mixing, or co-precipitating the compound and thesalt-forming acid or base in a conventional solvent, with or withoutalcohols or water, and evaporating or precipitating the resultingaddition salt, or by spray-drying the components together, or byco-precipitation, or by other known methods.

The compounds of the present invention are useful in pharmaceuticalcompositions for systemic administration to mammals including humans asa single agent, or as a primary or adjunct agent with any othermedication, chemical, drug or non-drug therapy, procedure, orcombination thereof.

The aforementioned administration of said compounds according to FormulaI is to be employed acutely, or as a single dose, or administeredintermittently, or on a regular schedule of unspecified duration, or bycontinuous infusion of unspecified duration, by an acceptable route ofadministration including, but not limited to, the oral, buccal,sublingual, intranasal, pulmonary, transdermal, rectal, vaginal,intradermal, intrathecal, intravenous, intramuscular, and/orsubcutaneous routes.

These pharmaceutical preparations can be employed in dosage forms suchas tablets, capsules, microcapsules, particles, pills, bulk or dividedpowders, granules, suppositories, sterile and parenteral oral solutionsor suspensions, sterile and non-parenteral solutions or suspensions,oral solutions or suspensions, disperse systems such as lotions, creams,ointments, gels, and the like, containing suitable quantities of theactive ingredient according to Formula I. Topical application can be inthe form of ointments, creams, lotions, jellies, sprays, douches,microneedle patches, and the like. For oral administration either solidor fluid dosage forms can be prepared with the compounds of Formula I.

For example, the compounds can be mixed with conventional ingredientssuch as dicalcium phosphate, magnesium aluminum silicate, magnesiumstearate, calcium sulfate, starch, talc, lactose, acacia,methylcellulose, polyvinylpyrrolidones, celluloses, and chemically andfunctionally similar materials as pharmaceutical excipients or carriers.A sustained release formulation may optionally be used. Capsules may beformulated by mixing the compound with a pharmaceutical diluent which isinert and loading this mixture into a capsule such as a hard gelatin orhydroxypropylmethylcellulose capsule having the appropriate size. Ifsoft capsules are desired, a solution, dispersion, or slurry of thecompound with an acceptable solvent, continuous phase, vegetable oil,other inert oil can be encapsulated by machine into a soft capsule, suchas a soft gelatin capsule.

Suspensions, syrups, and elixirs may be used for oral administration offluid dosage forms. A fluid preparation including oil may be used foroil soluble forms. A vegetable oil, such as corn oil, peanut oil, orsafflower oil, for example, together with flavoring agents, sweeteners,and any preservatives produces an acceptable fluid preparation. Asurfactant, sweetener and flavor may be added to water to form syrup forfluid dosages. Hydro-alcoholic pharmaceutical preparations may be usedthat have an acceptable sweetener, such as sugar, saccharine, or abiological sweetener and a flavoring agent in the form of an elixir.

Pharmaceutical compositions for parenteral and suppositoryadministration can also be obtained using techniques standard in theart. Another preferred use of the compounds is in a transdermalparenteral pharmaceutical preparation in a mammal such as a human.

In this case, the active compound or compounds can be present in thereservoir alone or in combination form with pharmaceutical carriers. Thepharmaceutical carriers acceptable for the purpose of this invention arethe carriers known in the art that do not adversely affect the drug, thehost, or the material comprising the drug delivery device or dosageform, or their containers or packaging. Suitable pharmaceutical carriersinclude: sterile water; saline; dextrose; dextrose in water or saline;condensation products of castor oil and ethylene oxide combining about30 to about 35 moles of ethylene oxide per mole of castor oil; liquidacid; lower alkanols; oils such as corn oil; peanut oil, sesame oil andthe like, with emulsifiers such as mono- or di-glyceride of a fattyacid, or a phosphatide, e.g., lecithin, and the like; glycols;polyalkylene glycols; aqueous media in the presence of a suspendingagent, for example, sodium carboxymethylcellulose; sodium alginate;poly(vinylpyrolidone); and the like, alone, or with suitable dispensingagents such as lecithin; polyoxyethylene stearate; and the like. Thecarrier may also contain adjuvants such as preserving stabilizing,wetting, and emulsifying agents and the like, with or without apenetration enhancer.

The terms “effective amount,” “therapeutic amount,” “therapeuticeffective amount” or “effective dose” mean the amount sufficient toelicit the desired pharmacological or therapeutic effect, thus resultingin the amelioration, prevention or treatment of the condition ordisorder. Thus, when treating an aforementioned nervous system disorder,an effective amount of compound is that amount sufficient to be absorbedinto the target tissues, to interact with the pharmacological targetperipherally, and to pass across the blood-brain barrier of the subjectand interact with relevant receptor sites in the brain of the subject.Prevention of the condition or disorder is manifested by delaying orpreventing the onset of the symptoms of the condition or disorder.Treatment of the condition or disorder is manifested by a decrease inthe symptoms associated with the condition or disorder, or a reductionin the recurrence of the symptoms of the condition or disorder.

The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,age, weight, diet, metabolic status, concurrent medications, species,and the manner in which the pharmaceutical composition is administered.Typically, the effective dose of compounds generally requiresadministering the compound in an amount ranging from about 0.1 to about500 mg/kg of the subject's weight. In an embodiment of the presentinvention, a dose of about 0.1 to about 300 mg/kg is administered once,intermittently, or daily, or indefinitely, or until symptoms associatedwith the condition or disorder cease. Preferably, about 0.05 to 50 mg/kgbody weight is administered per day. The required dose may be less whenadministered parenterally, transdermally, buccally, or rectally ascompared to other routes of administration.

EXAMPLES Example 1

In silico computerized modeling has revealed that examples of thebridged diindole compounds that are part of the subject matter of thepresent invention interact avidly with the NMDAR and its subunits, andmay serve as antagonists or partial antagonists to the NMDAR.

In Silico Ligands

Ligands were created using ChemBio3D Ultra 12. All ligands were drawnusing program defaults, and then the energy of each ligand was minimizedusing the MM2 energy minimization function before being saved in aformat suitable for docking in AutoDock4.2.

In Silico NMDA Model

Several crystal structures of NMDAr have been reported in the ProteinData Bank (PDB).

Selection of the crystal structure 2A5S, (Furukawa and Singh, Nature(2005) 438: 185-192) from PDB was based on the energy scores and bondangle analysis provided by PDB.org. The structure is composed of 284amino acids isolated from rat and represents the core ligand bindingdomain of NMDAR NR2A. The structure was co-crystallized with glutamateand determined to a resolution of 1.7 angstroms using X-ray diffraction.Using Accelrys Discovery Studio 3.1, all amino acid and chargecorrections were completed before the removal of the ligand and watermolecules. The file was then converted to MOL2, a suitable format foruse in AutoDock 4.2. Further analysis of the protein structure, usingDiscovery Studio 3.1, included determination of the ligand binding sitelocation. A cavity (FIGS. 1 through 3) was characterized and used todefine the coordinates of the grid box used in future dockingexperiments.

In Silico Docking to NMDAR NR2A

Grid Box Selection

The grid box was initially centered on the ligand glutamate and furtherrefined, using the coordinates determined previously in Discovery Studio3.1, in order to encompass the cavity of the protein in which glutamatebinding was characterized. The grid was centered at (21.5, 21.4, 36.1)with dimensions of:

Grid map x-dimension: 22.5 Angstroms

Grid map y-dimension: 22.5 Angstroms

Grid map z-dimension: 24.0 Angstroms

The gridbox was overlaid on the water-free ligand-free structure 2A5Sproduced in Discovery Studio 3.1 and processed using default AutoGridparameters in AutoDockTools 4.2.

AutoDock Parameters

AutoDock parameters were held constant when docking each ligand with theprepared NMDAR NR2A structure 2A5s. Each ligand was docked starting froma computer generated seed site to the protein within the gridboxpreviously described. Using default Lamarckian Algorithm settings set todefault short run in AutoDock 4, the energy was minimized. Optimumbinding energy and ligand conformation was then determined and recordedby AutoDock. This process was repeated 256 times for each ligand and thedata were compiled. The conformations were then grouped based on similarlocation and orientation with a 2 angstrom deviation to the mean of thepopulation as the grouping criteria.

Modeling Results

Bridged diindole compounds appear to bind to the NMDAR, including NR2subunits such as the NR2A subunit, in a specific orientation. Hydrogenbonding with THR174 may contribute to their biological andpharmacological effects. In an effort to elucidate the bindinginteractions of these compounds with NMDAR, the crystal structure of theNR2A subunit of NMDA was examined and the agonist, glutamate, bindingsite was identified and the binding cavity was characterized. Thebinding cavity is rich with hydrogen bond donors and acceptors and alsopossesses the ability to extensively interact with ligands bypi-bonding. The capacity of an NMDAR ligand, such as a bridged diindole,to interact with the receptor and its subunits appears to be dependentin part upon the presence of hydrogen bond-donating amines andpi-stacking aromatic ring systems, separated by a relatively flexiblebridging moiety, and in discrete orientations.

Two modelled bridged diindoles, thiodiindole and ethylenediindole, wereevaluated in this model. Such compounds retain hydrogen bond donors atthe nitrogens, while the large aromatic indole moieties have strongpi-stacking capacity. The binding energy of both thiodiindole, −10.42kcal/mole, and ethylenediindole, −10.88 kcal/mole, are more favorablethan representative diaminodiphenyl compounds, which were also evaluatedin tandem with bridged diindoles in order to compare the bindingaffinities of bridged diindoles with bridged diaminodiphenyls. Bothindole derivatives bound in the same orientation as the comparisondiaminodiphenyl compounds, and manifested hydrogen bonding with THR 174.Further, the binding affinities of representative bridged diindoles wereorders of magnitude higher than diaminodiphenyl comparisons. Thecomputational inhibition constants for diaminodiphenyls which bound in afavorable orientation and hydrogen bonded to THR 174 ranged from 7.38 to517.15 nM. As compared to analogous diaminodiphenyls, the diindolecompounds had ca. 100-fold increases in their computational inhibitionconstants. For example, 4,4′-diaminodiphenyl sulfide had an inhibitionconstant of 2.54 while the corresponding thiodiindole, had an inhibitionconstant of 23.01 nM. Likewise, 4,4′-ethylenedianiline had an inhibitionconstant of 1.19 whereas, with the corresponding ethylenediindole, theinhibition constant was calculated to be 10.54 nM. A summary of these insilico experiments, demonstrating the affinity and bindingcharacteristics of bridged diindoles, and those of bridgeddiaminodiphenyls as comparisons, with the NMDAR, including its subunits,is presented in the figures and tables.

TABLE 1 Ligand binding energy and root mean squared deviation of theligand root from a reference point in space within the crystallinestructure of NMDAr NR2a subunit. Binding Energy Ligand (Kcal/mole) RMS4,4′-methylene Bis(chloroaniline) −8.58 41.34 Dapsone −8.32 41.874,4′-methylene Bis(2,6-dimethylaniline) −8.28 42.294,4′-ethylenedianiline −8.08 43.23 Diaminobenzophenone −7.80 41.964,4′-diaminodiphenyl sulfide −7.63 43.42 4,4′-methylene Bis(cyclohexylamine) −7.49 44.22 Diaminodiphenyl methane −7.45 41.90 4,4′-methyleneBis(N,N-dimethylaniline) −7.35 39.50 4,4′-Oxydianiline −7.00 42.414,4′-(hexafluoroisopropylidene)dianiline −4.05 38.45 Ethylenediindole−10.88 44.58 Thiodiindole −10.42 43.87 N,N′-diacetylthiodianiline −9.3243.47

TABLE 2 Computational inhibition constant based on ligand interactionwith NMDAr NR2a subunit. Ligand Inhibition Constant 4,4′-methyleneBis(chloroaniline) 517.15 nM Dapsone 793.94 nM 4,4′-methyleneBis(2,6-dimethylaniline) 845.46 nM 4,4′-ethylenedianiline 1.19 uMDiaminobenzophenone 1.92 uM 4,4′-diaminodiphenyl sulfide 2.54 uM4,4′-methylene Bis(cyclohexyl amine) 3.25 uM Diaminodiphenyl methane3.43 uM 4,4′-methylene Bis(N,N-dimethylaniline) 4.12 uM4,4′-Oxydianiline 7.38 uM 4,4′-(hexafluoroisopropylidene)dianiline 1.07mM Ethylenediindole 10.54 nM Thiodiindole 23.01 nMN,N′-diacetylthiodianiline 146.95 nM

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While the present invention has been particularly shown and describedwith reference to the structure and methods disclosed herein and asillustrated in the drawings, it is not confined to the details set forthand this invention is intended to cover any modifications and changes asmay come within the scope and spirit of the following claims. Allpublications and patent literature described herein are incorporated byreference in entirety to the extent permitted by applicable laws andregulations.

What is claimed is:
 1. A method of therapeutically treating a nervoussystem disorder or condition selected from the group consisting ofepilepsies, seizures, conduction disturbances and electroconvulsivedisorders, pain, fibromyalgia, bipolar disorder, depression, autism,schizophrenia, Parkinson's disease, Alzheimer's disease and otherdementias, the method comprising administering to a subject in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprising: a compound having a structural formula asfollows, and a pharmaceutically acceptable excipient, carrier, ordiluent:

where, X is selected from the group consisting of —O—, —S—, —N(H)—,—Se—, —Si—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, (cis)-CH═CH—,(trans)-CH═CH—, —CH═CH—CH₂—, —CH₂—CH═CH—, —N═N—, —N═CH—, —CH═N—, —C(S)—,—N(H)S(O)—, —N(H)SO₂—, —N(H)O—, —N(H)S—, —S(O)—, —SO₂—, —PO₄—, —C(O)—,—CH₂—, —CF₂—, —C(CH₃)₂—, and a covalent bond; R¹ and R² are eachindependently selected from the group consisting of hydrogen, hydroxyl,carboxyl, amino, aminoalkyl, nitro, hydroxymethyl, hydroxyalkyl,acetate, propionate, butyrate, thiol, thioalkyl, nitrile, a halogen,trifluoromethyl, methoxy, ethoxy, phenyl, guanidino, amidino, amide,alkylamide, sulfate, phosphate, imidazole, thiazole, a substituted orunsubstituted C₁₋₁₀ alkyl, a substituted or unsubstituted branched C₃₋₁₀alkyl, a substituted or unsubstituted C₃₋₁₀ cycloalkyl, a substituted orunsubstituted arylalkyl.
 2. The method of claim 1, wherein thetherapeutically effective amount of the pharmaceutical compositioneffectively inhibits a function of a N-methyl-D-aspartate receptor(NMDAR) in the subject.
 3. The method of claim 1, wherein the subject ishuman.
 4. The method of claim 1, wherein the therapeutically effectiveamount is from about 0.1 mg/kg to about 300 mg/kg.
 5. The method ofclaim 1, wherein the compound comprises a thiodiindole orethylenediindole.
 6. A method of inducing or augmenting anesthesia, themethod comprising administering to a subject in need thereof atherapeutically effective amount of a pharmaceutical compositioncomprising: a compound having a structural formula as follows, and apharmaceutically acceptable excipient, carrier, or diluent:

where, X is selected from the group consisting of —O—, —S—, —N(H)—,—Se—, —Si—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, (cis)-CH═CH—,(trans)-CH═CH—, —CH═CH—CH₂—, —CH₂—CH═CH—, —N═N—, —N═CH—, —CH═N—, —C(S)—,—N(H)S(O)—, —N(H)SO₂—, —N(H)O—, —N(H)S—, —S(O)—, —SO₂—, —PO₄—, —C(O)—,—CH₂—, —CF₂—, —C(CH₃)₂—, and a covalent bond; R¹ and R² are eachindependently selected from the group consisting of hydrogen, hydroxyl,carboxyl, amino, aminoalkyl, nitro, hydroxymethyl, hydroxyalkyl,acetate, propionate, butyrate, thiol, thioalkyl, nitrile, a halogen,trifluoromethyl, methoxy, ethoxy, phenyl, guanidino, amidino, amide,alkylamide, sulfate, phosphate, imidazole, thiazole, a substituted orunsubstituted C₁₋₁₀ alkyl, a substituted or unsubstituted branched C₃₋₁₀alkyl, a substituted or unsubstituted C₃₋₁₀ cycloalkyl, a substituted orunsubstituted arylalkyl.
 7. The method of claim 6, wherein the compoundcomprises a thiodiindole or ethylenediindole.
 8. The method of claim 6,wherein the therapeutically effective amount of the pharmaceuticalcomposition effectively inhibits a function of a N-methyl-D-aspartatereceptor (NMDAR) in the subject.
 9. The method of claim 6, wherein thesubject is human.
 10. The method of claim 6, wherein the therapeuticallyeffective amount is from about 0.1 mg/kg to about 300 mg/kg.